Daptomycin (I) is a cyclic lipopeptide derived from a natural product of Streptomyces roseosporus. The daptomycin comprises an asparagine (Asn) residue in the D configuration. Daptomycin has been used for treating complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following gram-positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).

Daptomycin has also been used for treating Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. Daptomycin's bactericidal effects stem from its ability to rapidly depolarize the membrane potential of gram-positive bacteria, which causes inhibition of DNA, RNA and protein synthesis, and results in cell death. The bactericidal effect of daptomycin is rapid, with greater than 99.9% of both MRSA and MSSA bacteria dead in less than one hour.
Daptomycin has also been used for biofilm treatment including catheter-related bloodstream infections (CRBSI) due to gram-positive bacteria. Particularly, daptomycin may be used for central venous catheter salvage for S. aureus and S. epidermidis infected catheters.
Daptomycin is commercially available as CUBICIN® (“the CUBICIN® product”, Cubist Pharmaceuticals, Inc., Lexington, Mass.) and is supplied as a sterile, lyophilized powder. CUBICIN® is reconstituted in sodium chloride for parenteral injection. Stability studies have shown that the reconstituted solution is stable in a vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8° C. However, after this time, or at higher temperatures, daptomycin begins to degrade.
A major shortcoming of the commercially available daptomycin is that the reconstitution time of the CUBICIN® product is long and is typically in the range of about 15 to 45 minutes depending on the reconstitution procedure. This reconstitution time is not ideal in a therapeutic setting with respect to ease and efficiency of administration. Such long reconstitution time also increases the risk of inadvertent incomplete dissolution prior to administration and additionally increases the likelihood that the daptomycin will degrade prior to patient administration.
There are a number of daptomycin degradation products that have been identified. The major degradants of daptomycin are anhydro-daptomycin derivatives in which an α-aspartyl group is transpeptidated to an anhydrosuccinamido group, β-isomer of daptomycin in which the compound contains a β-aspartyl group instead of an α-aspartyl group and the lactone hydrolysis product of daptomycin in which one of the esters moieties is hydrolysed. The degradation pathway of daptomycin is described in U.S. Patent Publication No. 2007/191280.
High performance liquid chromatography (HPLC) of the reconstituted lyophilized powder can be used to determine the level of daptomycin relative to daptomycin degradants. Such comparison can thereby provide an indication of the stability of the daptomycin in the formulation. For example, International Patent Publication No. WO2011/063419 discloses solid daptomycin preparations with improved reconstitution times and stability profiles relative to the CUBICIN® product. This is achieved when sugars, such as sucrose, and a phosphate buffer are introduced into the formulation. The formulations have a pH of about 6.5 to about 7.5. The sugars used can be non-reducing sugars and are included in the formulations in an amount of about 2.5% w/v to about 25% w/v. For example, the sugars are included in amounts of 15% w/v and 20% w/v.
There is still a need for alternative solid lyophilized daptomycin formulations that exhibit rapid reconstitution times, preferably in less than about 5 minutes, in a pharmaceutically accepted diluent. Additionally, there still remains need for solid daptomycin formulations that exhibit rapid reconstitution times and have improved stability in both solid and reconstituted forms. Such a solid formulation would be advantageous, as it would provide for a longer shelf life, a lessened requirement for refrigerated storage and a reduced handling time in reconstitution of the product before use. Such a formulation would also provide for more rapid administration and a more reliable dosing of daptomycin due to the presence of fewer impurities resulting from daptomycin degradation.